Omeprazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl]sulphinyl]-1H-benzimidazole, is a compound of benzimidazole that can inhibit gastric secretion in mammals, so that it is useful for preventing and treating disorders related to secretion of gastric acid, such as gastric ulcers, duodenal ulcers, reflux oesophagitis, Zolliger-Ellison syndrome, etc. Other benzimidazole compounds with antiulcerous activity are pantoprazole, lansoprazole and rabeprazole.
Omeprazole, as other benzimidazole compounds of therapeutic interest, is labile in an acid medium, which creates a great number of problems when developing a pharmaceutical form meant for oral administration as said compound breaks down upon contact with the stomach contents, a strongly acidic medium. Its labile nature may be responsible for the variability in the intra- and inter-individual therapeutic response of omeprazole.
To prevent contact between compounds labile in an acid medium and gastric juice after oral administration of said compounds, solid pharmaceutical forms have been developed that are comprised of a core containing the compound labile in an acid medium and an outer layer that provides a gastro-resistant coating, which can be separated by one or more intermediate layers. In certain cases it is not possible to use conventional enteric coatings of acidic nature as the active compound would break down upon direct or indirect contact with said coating, as made manifest by a change in color and a degradation of the active compound over time.
There exist several ways of solving the problem of stability of the active compound. One of them consists of creating an alkaline environment around the benzimidazole compound labile in an acid medium, which is achieved by means of alkali salts of the benzimidazole compound and/or by incorporating an alkaline reacting compound in the gastro-resistant pharmaceutical preparation [see, for example, European Patent Application EP 0 244 380 and U.S. Pat. No. 4,786,505]. Another way of solving the problem of stability of the active compound is the creation of a physical barrier that manages to separate completely the active compound and the enteric layer, thereby preventing any degradation of the active compound, and involves the use of pharmaceutically acceptable excipients with the exception of those giving an alkaline reaction [see, for example, European Patent EP 0 773 025].
Patent application WO 96/01623 describes a multiple unit tableted dosage form containing omeprazole or an alkali salt thereof, consisting of units arranged in layers that contain the active compound individually coated with an enteric coating. Such units arranged as enteric coated layers are mixed with excipients for tablets and are tableted together.